The past decade has brought unprecedented progress in understanding the genetics of epithelial ovarian cancer (EOC), but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. EOC is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of EOC. Despite the importance of epigenetic regulators in EOC, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Dr. Zhang’s past programmatic contributions have created new concepts on the impact ...

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The past decade has brought unprecedented progress in understanding the genetics of epithelial ovarian cancer (EOC), but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. EOC is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of EOC. Despite the importance of epigenetic regulators in EOC, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Dr. Zhang’s past programmatic contributions have created new concepts on the impact of epigenetics in the disease and moved the field to a new level of sophistication. Consequently, the therapeutic strategies developed by his laboratory are now entering clinical testing as potential practice-changing treatments. However, the full potential of targeting epigenetic dysregulation in EOC remains to be realized. Accordingly, the overarching goal of the application is to leverage epigenetic mechanisms to address unmet clinical needs in EOC through integrated approaches. The objectives of the application are to: 1) develop new therapeutic strategies for rare histosubtypes of EOCs based on genetic mutations in epigenetic regulators ARID1A and PPP2R1A, and 2) leverage epigenetic alterations associated with the tumor microenvironment to develop EOC therapeutic strategies. The proposed studies are of high impact because mechanistic understanding of the role of epigenetic regulators in EOC will reveal actionable therapeutic targets with precision that may ultimately eradicate EOC, the most lethal gynecological malignancy in the United States. Since genetic alterations in epigenetic regulators are driver events across human cancers, the mechanistic insights and therapeutic approaches revealed from the current studies will have broad implications for other cancers.

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